Lenalidomide chemically known as 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione is a non-polypeptide compound which decrease the levels of TNF [alpha]. It was approved by US FDA in 2005 for the patients and it is commercially sold as REVLIMID™ by Celgene.
TNF[alpha] is a candidate inducing angiogenesis in inflammation, wound repair, and tumor growth. TNF [alpha] production also has been associated with cancerous conditions, particularly induced tumors. It also plays a role in the area of chronic pulmonary inflammatory diseases. The deposition of silica particles leads to silicosis, a disease of progressive respiratory failure caused by a fibrocystic reaction. Lenalidomide inhibits tumor angiogenesis, tumor secreted cytokines and tumor proliferation through the induction of apoptosis. Lenalidomide has also shown efficacy in the class of hematological disorders known as myelodysplastic syndromes (MDS).
Lenalidomide and its process are disclosed in U.S. Pat. No. 5,635,517. The process for synthesis of Lenalidomide includes reacting methyl 2-bromomethyl-3-nitrobenzoate with 2,6 dioxopiperidin-3-ammonium chloride in presence of DMF and triethylamine to obtain 3-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)-piepridine-2,6-dione and hydrogenating the nitro intermediate, 3-(1-oxo-4-nitro-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, at 50 psi pressure using 10% Pd/C catalyst in 1,4-dioxane. The residue is crystallized from ethyl acetate and further from dioxane/ethyl acetate mixture to yield about 36% of the product.
WO2006/028964 describes the preparation of Lenalidomide which involves the preparation of the nitro intermediate comprising coupling of an L-glutamine methyl ester with methyl-2-bromomethyl-3-nitro benzoate in acetonitrile and cyclising the resultant N-(1-oxo-4-nitro-isoindol-2-yl)-L-glutamine methyl ester. The nitro intermediate is then reduced with Pd/C in methanol followed by cyclisation under acidic conditions to yield 51% of Lenalidomide.
PCT publication No. WO 2009/114601 discloses improved processes for the preparation of substantially pure Lenalidomide. According to the publication, Lenalidomide can be prepared by reacting methyl 2-halomethyl-3-nitrobenzoate with α-amino glutarimide hydrochloride in the presence of triethylamine and N-methylpyrrolidone (NMP) or acetonitrile solvent to obtain 3-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)-piepridine-2,6-dione and then hydrogenating with palladium carbon in presence of a solvent selected from alcohols, ketonic solvents, DMF, DMSO, DMAc and an acid selected from inorganic and organic acids.
Indian Application No. 047/CHE/2006 which was published on Nov. 23, 2007, discloses a process which comprises hydrogenating 3-(4-nitro-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione using 10% Pd on carbon in a mixture of solvents comprising methanol and N,N-dimethylformamide to provide Lenalidomide.
PCT Publication No. WO 2010/100476 ('476 patent) discloses a process for the preparation of Lenalidomide. According to the publication, Lenalidomide can be prepared by catalytic reduction of 3-(1-oxo-4-nitro-1,3-dihydro-isoindol-2-yl)-piepridine-2,6-dione with palladium carbon preferably in acetonitrile and methanol. WO '476 also discloses a process for the preparation of 3-(1-oxo-4-nitro-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione by reacting 3-amino-piperidine-2,6-dione hydrochloride with methyl 2-bromomethyl-3-nitro-benzoate in N,N-dimethylformamide.
The prior art processes suffer from the following disadvantages; viz. (i) low yield of the product; (ii) low yield of the nitro intermediate and (iii) in the use of large amount of solvents that makes the processes commercially not viable.
Further, various polymorphic forms of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (generically known as Lenalidomide) are mentioned in PCT publication WO2005/023192. Polymorphic forms viz. Form A in anhydrous form with no water content, Form B as hemihydrate with moisture content 3.1%, Form C as hemisolvate of acetone, Form D solvated with water and acetonitrile. Further, Form E is a dehydrate with moisture content of 11.8%, Form F is an unsolvated material obtained by complete dehydration of Form E, Form G is an unsolvated form obtained by slurrying Form B and Form E in THE Form H is a crystalline solid hydrated with 0.25 moles of water.
Further, WO2005/023192 discloses the hemihydrate Form B obtained by crystallization from many solvents, including, but not limited to hexane, toluene and water. It is further described that Form B is the desired polymorphic form for active pharmaceutical ingredient (API).
US2014/0121245 relates to anhydrous polymorphic Form I of Lenalidomide. The synthetic process for Lenalidomide comprises side chain bromination of methyl 2-methyl-3-nitro-benzoate with NBS in suitable solvents selected from halogenated hydrocarbons; alkylation followed by cyclisation of methyl 2-bromomethyl-3-nitro-benzoate with d1,3-Aminoglutarimide in solvents such as dimethylformamide, methanol, ethanol, acetonitrile to obtain 3-(4-nitro-1-oxo-1,3dihydro-isoindol-2-yl)-piperidine-2,6-dione; catalytic hydrogenation of 3-(4-nitro-1-oxo-1,3dihydro-isoindol-2-yl)-piperidine-2,6-dione in solvents such as dimethylformamide, methanol, ethanol, isopropyl alcohol or mixture of these solvents to obtain Lenalidomide polymorphic Form I.
In the alternate synthesis disclosed in US'245, Form-I is obtained by suspending the wet Lenalidomide cake, which is obtained directly after filtration of the catalyst from the reaction mass, in solvents such as isopropyl alcohol, dimethylformamide and acetonitrile followed by reducing or completely distilling the solvents at temperatures varying 65° C. to 110° C. under vacuum or without vacuum and then finally drying at temperature varying from 40-110° C. either under vacuum or without vacuum. Also, the anhydrous polymorphic Form-I of Lenalidomide is obtained by filtration and drying at temperature varying from 40-110° C. either under vacuum or without vacuum after azeotropically distilling the solvent toluene completely or partially with or without vacuum, at temperatures varying 65° C. to 110° C.
US'245 further reports that anhydrous polymorphic Form I of Lenalidomide can also be prepared by taking the hydrated Form B or Form E of Lenalidomide in a solvent such as isopropyl alcohol or in acetonitrile. The polymorphic Form I of Lenalidomide can also be prepared by taking the hydrated form of Lenalidomide in a solvent such as toluene, xylene or cyclohexane wherein the water in the product is completely separated by azeotropic distillation.
Also disclosed therein is polymorphic Form-B and its process for preparation comprising reacting polymorphic Form I with molar equivalent of hydrochloric acid and dissolving in water; adding activated charcoal to the solution, filtering, neutralizing and adjusting the pH to 7.5 to 8.0 with a suitable base to get the Lenalidomide precipitated followed by washing and drying under vacuum at temperature 65° C. to 110° C.
Amorphous Lenalidomide is disclosed in PCT publication No. WO 2009/114601.
PCT publication No. WO 2010/056384 discloses N,N-dimethylformamide solvate and dimethylsulfoxide solvate of Lenalidomide.
Anhydrous crystalline Form of Lenalidomide is disclosed in PCT publication No. WO 2010/061209. The process includes dissolving Lenalidomide in a solvent selected from the group comprising straight chained or branched C1-C5 alcohols, aliphatic ketones, and cyclic ethers or mixtures thereof and isolating the resultant crystalline solid. The publication also disclosed a process for conversion of anhydrous crystalline Form of Lenalidomide into prior art Lenalidomide crystalline form B (as disclosed in WO 2005/023192) comprising the steps of: (a) dissolving or suspending the anhydrous crystalline form in a mixture of a polar organic solvent and water; (b) causing the desired Form B to precipitate from the solution or suspension in step (a); and (c) isolating the solid crystalline Form.
WO2011061611 relates to process for preparation of polymorphic Form B of Lenalidomide which includes reducing 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-nitroisoindoline with Pd/C in N,N-dimethylformamide to obtain a N,N-dimethylformamide solvate of Lenalidomide; treating the N,N-dimethylformamide solvate of Lenalidomide so obtained with water; and isolating polymorphic Form B of Lenalidomide from the reaction mixture thereof.
In view of the above, there remains a need in the art to provide an improved process for synthesis of Lenalidomide which is efficient and industrially preferable.
Further, it is well known that poor solubility of an API can affect its bioavailability thereby affecting the dosage size in a pharmaceutical formulation. Since the polymorphic forms disclosed in the prior art are susceptible to conversion in an aqueous environment which is undesirable in terms of stability and storage capacity, the present inventors felt a need to provide more stable polymorphic Forms of Lenalidomide which has stability upon storage and during manufacture and in the presence of water and other aqueous solvent systems with desirable aqueous solubility.
It is therefore the other object of the invention to provide an improved method for preparation of Lenalidomide polymorphic Form B and Form I and to the process for conversion of polymorphic Form B to polymorphic Form I.